Progression of regional atrophy in the left hemisphere contributes to clinical and cognitive deterioration in multiple sclerosis: A 5-year study

Abstract

In this longitudinal study, we investigated the regional patterns of focal lesions accumulation, and gray (GM) and white matter (WM) atrophy progression over a five-year follow-up (FU) in multiple sclerosis (MS) patients and their association with clinical and cognitive deterioration. Neurological, neuropsychological and brain MRI (dual-echo and 3D T1-weighted sequences) assessments were prospectively performed at baseline (T0) and after a median FU of 4.9 years from 66 MS patients (including relapse-onset and primary progressive MS) and 16 matched controls. Lesion probability maps were obtained. Longitudinal changes of GM and WM volumes and their association with clinical and cognitive deterioration were assessed using tensor-based morphometry and SPM12. At FU, 36/66 (54.5%) MS patients showed a significant disability worsening, 14/66 (21.2%) evolved to a worse clinical phenotype, and 18/63 (28.6%) developed cognitive deterioration. At T0, compared to controls, MS patients showed a widespread pattern of GM atrophy, involving cortex, deep GM and cerebellum, and atrophy of the majority of WM tracts, which further progressed at FU (P < 0.001, uncorrected). Compared to stable patients, those with clinical and cognitive worsening showed a left-lateralized pattern of GM and WM atrophy, involving deep GM, fronto-temporo-parieto-occipital regions, cerebellum, and several WM tracts (P < 0.001, uncorrected).GM and WM atrophy of relevant brain regions occur in MS after 5 years. A different vulnerability of the two brain hemispheres to irreversible structural damage may be among the factors contributing to clinical and cognitive worsening in these patients. Hum Brain Mapp 38:5648-5665, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: MRI; atrophy progression; gray matter; multiple sclerosis; white matter.

Figure 1

Regional damage in multiple sclerosis (MS) patients versus healthy controls (HC) at baseline (T0) and follow‐up. (a) Representative images showing (1) T2 (red color‐coded) and (2) T1 (green color‐coded) lesion probability maps (LPMs) and statistical parametric mapping (SPM) analysis showing regions of (3) gray matter (GM) (yellow color‐coded) and (4) white matter (WM) (blue color‐coded) volume loss superimposed on the customized GM template in MS patients versus HC at T0 (P < 0.001 uncorrected; cluster extent = 10 voxels). The LPMs are thresholded to show voxels in which lesion frequency of 5% is present, up to a maximum lesion frequency of 45% for T2 LPM and of 35% for T1 LPM. (b) Representative images showing areas of increased frequency of (1) T2 (red color‐coded) and (2) T1 (green color‐coded) lesions in MS patients and regions of (3) GM (yellow color‐coded) and (4) WM (blue color‐coded) atrophy after 5 years superimposed on the customized GM template in MS patients versus HC (P < 0.001 uncorrected; cluster extent = 10 voxels). Images are in neurological convention. See text for further details. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Evolution of regional damage in the main study subgroups. Representative images showing areas of increased frequency of (1) T2 (red color‐coded) and (2) T1 (green color‐coded) lesions and regions of (3) gray matter (GM) (yellow color‐coded) and (4) white matter (WM) (blue color‐coded) atrophy after 5 years superimposed on the customized GM template according to clinical (EDSS score and phenotype change) and cognitive evolution at follow‐up (P < 0.001 uncorrected; cluster extent = 10 voxels). Images are in neurological convention. See text for further details. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Difference of regional damage progression in worsened versus stable multiple sclerosis (MS) patients. Statistical parametric mapping (SPM) analysis showing areas of increased frequency of (1) T2‐hyperintense lesions (red color‐coded) and (2) T1‐hypointense lesions (green color‐coded), as well as regions of (3) gray matter (GM) (yellow color‐coded) and (4) white matter (WM) (blue color‐coded) atrophy after 5 years superimposed on the customized GM template in worsened versus stable MS patients according to the different outcomes. Left column (a): EDSS worsened versus stable; middle column (b): MS patients with vs without phenotype change; right column (c): cognitively worsened versus cognitively stable (P < 0.001 uncorrected; cluster extent = 10 voxels). Images are in neurological convention. See text for further details. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Lateralization index in the main study subgroups. Graphical representation of (a) total number of voxels and (b) lateralization index of number of voxels in the left and right hemispheres showing increased frequency of T2‐hyperintense lesions (red color‐coded) and T1‐hypointense lesions (green color‐coded), and gray matter (GM) (yellow color‐coded) and white matter (WM) (blue color‐coded) atrophy after 5 years in worsened versus stable multiple sclerosis (MS) patients according to the different outcomes. The lateralization index of between‐group differences was calculated as (total number of significant left hemisphere voxels − total number of significant right hemisphere voxels)/(total number of significant brain voxels) × 100. See text for further details. [Color figure can be viewed at http://wileyonlinelibrary.com]